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The leishmanicidal activity of artemisinin is mediated by cleavage of the endoperoxide bridge and mitochondrial dysfunction

Published online by Cambridge University Press:  05 November 2018

Sritama De Sarkar ,
Deblina Sarkar ,
Avijit Sarkar ,
Aishwarya Dighal ,
Sasanka Chakrabarti ,
Katrin Staniek ,
Lars Gille Open the ORCID record for Lars Gille [Opens in a new window]  and
Mitali Chatterjee Open the ORCID record for Mitali Chatterjee [Opens in a new window]
Sritama De Sarkar
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Deblina Sarkar
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Avijit Sarkar
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Aishwarya Dighal
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Sasanka Chakrabarti
Affiliation:
Department of Biochemistry, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
Katrin Staniek
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
Lars Gille*
Affiliation:
Department of Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
Mitali Chatterjee
Affiliation:
Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata-700 020, India
*
Author for correspondence: Lars Gille, E-mail: [email protected] and Mitali Chatterjee, E-mail: [email protected]
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Abstract

Endoperoxides kill malaria parasites via cleavage of their endoperoxide bridge by haem or iron, leading to generation of cytotoxic oxygen-centred radicals. In view of the Leishmania parasites having a relatively compromised anti-oxidant defense and high iron content, this study aims to establish the underlying mechanism(s) accounting for the apoptotic-like death of Leishmania promastigotes by artemisinin, an endoperoxide. The formation of reactive oxygen species was confirmed by flow cytometry and was accompanied by inhibition of mitochondrial complexes I–III and II–III. However, this did not translate into a generation of mitochondrial superoxide or decrease in oxygen consumption, indicating minimal impairment of the electron transport chain. Artemisinin caused depolarization of the mitochondrial membrane along with a substantial depletion of adenosine triphosphatase (ATP), but it was not accompanied by enhancement of ATP hydrolysis. Collectively, the endoperoxide-mediated radical formation by artemisinin in Leishmania promastigotes was the key step for triggering its antileishmanial activity, leading secondarily to mitochondrial dysfunction indicating that endoperoxides represent a promising therapeutic strategy against Leishmania worthy of pharmacological consideration.

Keywords

ArtemisininendoperoxidesLeishmaniamitochondriamitochondrial membrane potentialreactive oxygen species (ROS)
Type
Research Article
Information
Parasitology , Volume 146 , Issue 4 , April 2019 , pp. 511 - 520
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Copyright
Copyright © Cambridge University Press 2018 

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